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Nitric Oxide Induces Airway Smooth Muscle Cell Relaxation by Decreasing the Frequency of Agonist-Induced Ca2+ Oscillations

Nitric Oxide Induces Airway Smooth Muscle Cell Relaxation by Decreasing the Frequency of Agonist-Induced Ca2+ Oscillations

Jose F Perez-Zoghbi, Yan Bai, Michael J Sanderson

J Gen Physiol. 2010 Mar;135(3):247-59.

PMID: 20176853

Abstract:

Nitric oxide (NO) induces airway smooth muscle cell (SMC) relaxation, but the underlying mechanism is not well understood. Consequently, we investigated the effects of NO on airway SMC contraction, Ca(2+) signaling, and Ca(2+) sensitivity in mouse lung slices with phase-contrast and confocal microscopy. Airways that were contracted in response to the agonist 5-hydroxytryptamine (5-HT) transiently relaxed in response to the NO donor, NOC-5. This NO-induced relaxation was enhanced by zaprinast or vardenafil, two selective inhibitors of cGMP-specific phosphodiesterase-5, but blocked by ODQ, an inhibitor of soluble guanylyl cyclase, and by Rp-8-pCPT-cGMPS, an inhibitor of protein kinase G (PKG). Simultaneous measurements of airway caliber and SMC [Ca(2+)](i) revealed that airway contraction induced by 5-HT correlated with the occurrence of Ca(2+) oscillations in the airway SMCs. Airway relaxation induced by NOC-5 was accompanied by a decrease in the frequency of these Ca(2+) oscillations. The cGMP analogues and selective PKG activators 8Br-cGMP and 8pCPT-cGMP also induced airway relaxation and decreased the frequency of the Ca(2+) oscillations. NOC-5 inhibited the increase of [Ca(2+)](i) and contraction induced by the photolytic release of inositol 1,4,5-trisphosphate (IP(3)) in airway SMCs. The effect of NO on the Ca(2+) sensitivity of the airway SMCs was examined in lung slices permeabilized to Ca(2+) by treatment with caffeine and ryanodine. Neither NOC-5 nor 8pCPT-cGMP induced relaxation in agonist-contracted Ca(2+)-permeabilized airways. Consequently, we conclude that NO, acting via the cGMP-PKG pathway, induced airway SMC relaxation by predominately inhibiting the release of Ca(2+) via the IP(3) receptor to decrease the frequency of agonist-induced Ca(2+) oscillations.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP146724825	NOC-5		146724-82-5	Price

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